The repeated use of psychostimulants produces long-term changes in brain chemistry and behavior that are thought to contribute to persistent and compulsive drug use. Long-term adaptations are also observed in response to other drugs of abuse including opiates and alcohol. Our studies seek to understand the mechanisms, both at the systems and cellular level, which underlie these changes. Included in this goal is the identification of biological factors that may predispose certain individuals to abuse psychoactive drugs and pharmacotherapies that may be effective in the treatment of drug and alcohol addiction. Our studies have suggested an important role of endogenous opioid peptides in modulating dopamine neurons in the brain upon which drugs of abuse act to affect and subsequently control behavior. We have shown that the release of the opioid peptide, dynorphin, the endogenous ligand for the kappa opioid receptor, is increased in response to the use of amphetamine and cocaine and that this increase opposes alterations in behavior and presynaptic dopamine neurotransmission that occur as a consequence of psychostimulant use. Using biochemical and immunocytochemical approaches we have shown that the activation of the kappa opioid receptor causes marked changes in the trafficking of the dopamine transporter, a membrane-bound protein that is a key substrate upon which psychostimulants act. Our studies suggest that the activation of the kappa opioid receptor increases the trafficking of the transporter from the cytosol to the plasma membrane and that this action may be one mechanism underlying the ?cocaine-antagonist-like? effects of drugs that activate this opioid receptor subtype. Data suggesting that kappa agonists may exert their effects via the activation of two kinases (mitogen activated protein kinase and phosphoinositol ?3 kinase) that regulate cytoskeletal dynamics has also been obtained. We have also shown that pharmacological inactivation or genetic ablation of dynorphin or its receptor results in increased vulnerability to the behavioral and neurochemical effects of cocaine. Our more recent studies have shown that this vulnerability extends to another drug of abuse, morphine and that tolerance to the analgesic effects of morphine, can be reversed by administration of a peptide that binds to and complexes with an N-terminal sequence of the dynorphin molecule. Using pharmacological and genetic approaches to selectively inactivate other opioid receptor types (e.g., mu ? and delta-), we have begun to examine whether dysregulation of specific opioid receptor systems affects basal and drug-evoked neurotransmission in two dopamine- rich brain regions implicated in mediating the behavioral effects of drugs of abuse (n. accumbens and ventral pallidum). In parallel studies, intravenous drug self-administration is being used in conjunction with in vivo techniques for the quantification of peptide and neurotransmitter release in the same animal to determine the role of opioid / dopamine system interactions in mediating individual differences in vulnerability to acquire, maintain and reinstate compulsive drug-seeking behavior.